2002 Progress Report: Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac Ischemia

EPA Grant Number: R827353C008
Subproject: this is subproject number 008 , established and managed by the Center Director under grant R827353
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: EPA Harvard Center for Ambient Particle Health Effects
Center Director: Koutrakis, Petros
Title: Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac Ischemia
Investigators: Godleski, John J.
Current Investigators: Godleski, John J. , Gonzalez-Flecha, Beatriz , Wellenius, Gregory
Institution: Harvard University
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2002 through May 31, 2003
Project Amount: Refer to main center abstract for funding details.
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

The main objective of this research project is to investigate the effects of concomitant gaseous co-pollutants, particle size, and particle composition.

Progress Summary:

To date, a large number of animal exposure studies have been completed. These studies have been totally or partially funded by the Center.

We have examined whether short term exposures to concentrated ambient particles (CAPs) can cause pulmonary inflammation in normal rats and rats with chronic bronchitis (Saldiva, et al., 2002); Four groups of animals were studied: (1) air-treated, filtered air-exposed (air-sham); (2) SO2-treated (chronic bronchitis (CB)), filtered air exposed (CB-sham); (3) air-treated, CAPs-exposed (air-CAPs); and (4) SO2-treated, CAPs exposed (CB-CAPs). Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) and by measuring the numerical density of neutrophils (Nn) in the alveolar walls in the centri-acinar and in the peripheral segments of the pulmonary acinus. CAPs induced a significant increase in BAL neutrophils and in Nn in the lung tissue. Greater Nn was observed in the central compared to peripheral regions of the lung. A significant, dose-dependent association was found between V and Br concentrations and both BAL neutrophils and Nn. BAL neutrophils and protein were also correlated with Pb, SO42-, Si, organic carbon, and elemental carbon concentrations. Results demonstrate that short-term exposures to CAPs from Boston induce a significant inflammatory reaction in rat lungs, which depends on particle composition.

For the same animals we examined whether short-term CAPs exposures altered the morphology of small pulmonary arteries (Batalha, et al., 2002). Histologic slides were prepared from random sections of lung lobes and coded for blinded analysis. The lumen/wall area ratio (L/W) was determined morphometrically on transverse sections of small pulmonary arteries. When all animal data (normal and CB) were analyzed together, the L/W ratios decreased as concentrations of fine particle mass, silicon, lead, sulfate, elemental carbon and organic carbon increased. In separate univariate analyses, the association for sulfate was significant only in normal rats, whereas silicon was significantly associated in both CB and normal rats. In multivariate analyses including all particle factors, the association with silicon remained significant. Our results indicate that short-term CAPs exposures (median 182.7, range 73.5-733.0 µg/m3) can induce vasoconstriction of small pulmonary arteries in normal and CB rats. This effect was correlated with specific particle components, and suggests that the pulmonary vasculature might be an important target for ambient air particle toxicity.

With the repeated finding in both dogs and rats of increased pathologic responses to inhalation of concentrated urban air particles and the identification of silicon (as silicate) as an element associated with some of these responses, we carried out studies to determine whether there is a change in toxicity as silicon-containing particles pass through the Harvard Ambient Particle Concentration (HAPC) (Savage, et al., submitted 2002). Using silicate rich Mt. St. Helen's volcanic ash, (MSHA) we exposed three groups of Sprague-Dawley rats by inhalation for 6 hours to filtered air, MSHA, or MSHA passed though the HAPC. Twenty-four hours following exposure, BAL was performed to assess total cell count, differential cell count, and protein, lactate dehydrogenase, and n-beta glucosaminidase levels. Peripheral blood was examined for packed cell volume, total protein, total white cells, and differential cell count. In another group of rats L/W ratios were determined on the pulmonary vessels. No significant differences were observed among any of the groups in any parameter measured. Power calculations indicate sufficient power to find differences among all of these parameters. Scanning electron microscopy and x-ray analysis was performed to identify particles in the lungs, revealing silicates typical of MSHA throughout the lung. Our findings suggest that particles passing through the HAPC have no change in their toxic potential in an exposure setting where substantial particle deposition has occurred. This study validates the use of the HAPC as a method of creating concentrated aerosol of fine urban air particles without altering their physical properties or potential for toxic insult.

Based on these findings, we postulated that the silicates are traveling in CAPs with a more toxic partner that is responsible for the pathologic responses to exposure that our group has documented. Silicates identified in these studies associate strongly with markers of soil dust such as calcium and aluminum, and there is a fraction of soil particles found below 2.5 microns (the upper limit of concentration by the HAPC). The remaining mass of this factor most likely includes urban road dust, which is enriched with combustion derived materials, organic semi-volatile compounds, latex, sulfate and nitrate, and tire and brake derived particles. Bioaerosols such as pollen and fungal spores also are found in road dust. Accordingly, we have begun instillation studies of road dust from a major urban thoroughfare (located between the HAPC inlet and the adjacent street) gathered on a polyurethane foam (PUF) sampler (0.7 – 7 micron size selection) to examine the relative toxicity of this material. We exposed 5 groups of Sprague-Dawley rats by intratracheal instillation to either saline, saline plus PUF, 0.01 mg/kg road dust, 0.1 mg/kg road dust, or 1 mg/kg road dust. Twenty-four hours following exposure, we performed BAL to assess total cell count, differential cell count, total protein, lactate dehydrogenase, and n-beta glucosaminidase. Blood was examined for hematocrit, total protein, total white cell count, and differential. Intratracheal instillation of glutaraldehyde was performed for pulmonary vascular morphometric analysis, and scanning electron microscopy and x-ray analysis of particles in the lung. Our initial findings show significant differences in differential cell count from BAL fluid, and the complete analysis of these studies is in progress.

In the context of this project, we have started to support and include the innovative work of Dr. Beatriz Gonzales-Flecha's laboratory. The laboratory's studies focus on oxidant mechanisms to explain cardiac responses. Dr. Gonzales-Flecha and her collegues have reported rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart associated with ambient particle exposures Gurgueira et al. (Gurgueira, et al., 2002). More recently, they confirmed the role of oxidants in the inflammatory response to CAPs adult rats. The experimental protocol included exposures to filtered air (Sham) or CAPs aerosols (CAPs, 5 hours exposure, average mass concentration: 1,100 ± 300 µg/m3) in the presence or absence of 50 mg/Kg intraperitoneal N-acetyl-L-cysteine (NAC). BAL, tissue and blood samples were collected 24 hours after exposure. The results of this study suggested a dramatic increase of polymorphonuclear leukocytes (PMN) number in BAL as a result to CAPs exposures. This increase was mediated by oxidants, since pre-administration of NAC effectively prevented PMN influx into the lung. Additional recent data support our hypotheses that CAPs promotes oxidant-mediated inflammation in the lung and that sympathetic activation after CAPs deposition in the lung is critical for CAPs cardiotoxicity. Studies will continue in this important area in the coming year.

Furthermore, we have developed a rat model of acute myocardial infarction (MI) to study the effects of particles on ischemia-induced arrhythmias (Wellenius, et al., 2002). In these studies, a left-ventricular MI is surgically induced in Sprague-Dawley rats by thermocoagulation of the left coronary artery. Using this model, we have shown that 1 hour exposure to residual oil fly ash (ROFA), but not carbon black or room air, increased the frequency of premature ventricular complexes (PVC) in a significant number (80 percent) of animals with pre-existing ventricular arrhythmias (Wellenius, et al., 2002). We are now using this model to determine if a similar effect is observed following CAPs exposure and if this effect is modified by exposure to carbon monoxide (CO). Within 12-18 hours after surgery, diazepam-sedated animals were exposed to filtered air (FA) for 1 hour (baseline period), either FA only (n=53), FA and CO (n=22), CAPs only (n=68), or CAPs and CO (n=24) for 1 hour (exposure period), and filtered air for an additional hour (recovery period). Electrocardiograms were recorded and the number of PVCs in each period was determined. Arrhythmia counts were analyzed by repeated-measures Poisson regression with control for overdispersion. CAPs mass ranged from 60.3 to 2,202.5 µg/m3 with a mean of 566 µg/m3 (n=29 days). The target CO concentration was 35 ppm. The mean CO concentration in the FA and CO chamber was 38.4±4.3 ppm (mean±standard error; n=13 days) and the mean concentration is the CAPs and CO chamber was 38.8±3.1 ppm (n=13 days). Exposure to CO was associated with a 71.9 percent (p=0.01) decrease in PVC frequency during the exposure period and a 51.8 percent (p=0.17) decrease during the recovery period. In contrast, exposure to CAPs had no effect on PVC frequency during either the exposure or recovery periods. There also was no evidence of interaction between the effects of CAPs and CO. Results were qualitatively similar when only animals with a transmural MI were considered. However, CO had no effect on PVC frequency in animals with a subepicardial MI. We conclude that: (1) the arrhythmogenic effects associated with ROFA exposure are not observed with CAPs exposure; (2) CO monoxide exposure decreases PVC frequency in rats with transmural MI; and (3) the effect of CO on arrhythmia frequency is not modified by exposure to CAPs.

References:

Lippman M, Frampton M, Schwartz J, Dockery DW, Schlesinger R, Koutrakis P, Froines J. The EPA's Particulate Matter (PM) Health Effects Research Centers Program: a mid-course (2 1/2 year) report of status, progress, and plans. Environmental Health Perspectives (in press, 2003).

Savage ST, Lawrence J, Katz T, Stearns R, Godleski JJ. Does the Harvard/EPA ambient particle concentrator change the toxic potential of particles? Journal of the Air and Waste Management Association (submitted, 2002).

Gurgueira S, Lawrence J, Coull BA, Krishna Murthy GG, Gonzalez-Flecha B. Environmental Health Perspectives 2002;110:749-755.

Future Activities:

Future activities will continue to investigate the effects of concomitant gaseous co-pollutants, particle size, and particle composition. To date, a large number of animal exposure studies have been completed. These studies have been totally or partially funded by the Center.


Journal Articles on this Report : 2 Displayed | Download in RIS Format

Other subproject views: All 4 publications 4 publications in selected types All 4 journal articles
Other center views: All 200 publications 198 publications in selected types All 197 journal articles
Type Citation Sub Project Document Sources
Journal Article Wellenius GA, Saldiva PHN, Batalha JRF, Krishna Murthy GG, Coull BA, Verrier RL, Godleski JJ. Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction. Toxicological Sciences 2002;66(2):327-335. R827353 (Final)
R827353C008 (2001)
R827353C008 (2002)
R827353C008 (2003)
R827353C008 (Final)
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  • Journal Article Wellenius GA, Coull BA, Godleski JJ, Koutrakis P, Okabe K, Savage ST, Lawrence JE, Krishna Murthy GG, Verrier RL. Inhalation of concentrated ambient air particles exacerbates myocardial ischemia in conscious dogs. Environmental Health Perspectives 2003;111(4):402-408. R827353 (Final)
    R827353C008 (2001)
    R827353C008 (2002)
    R827353C008 (2003)
    R827353C008 (Final)
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  • Supplemental Keywords:

    air pollution, air pollutants, particulates, particles, particulate matter, PM, fine particulates, PM2.5, health effects, particle size, particle composition, gaseous pollutants, cardiac ischemia, cardiovascular effects, cardiovascular disease, heart disease, pulmonary inflammation, chronic bronchitis, exposure, concentrated ambient particles, CAPs, silicon, lead, sulfate, elemental carbon, organic carbon, concentrated urban air particles, fine urban air particles, cardiotoxicity, toxicity, lung inflammation, premature ventricular complexes, arrhythmogenic effects, myocardial infarction., RFA, Health, Scientific Discipline, Air, Geographic Area, particulate matter, Toxicology, air toxics, Environmental Chemistry, Epidemiology, State, Risk Assessments, Microbiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Disease & Cumulative Effects, Environmental Monitoring, Children's Health, genetic susceptability, tropospheric ozone, Atmospheric Sciences, Molecular Biology/Genetics, Biology, Environmental Engineering, ambient air quality, health effects, interindividual variability, molecular epidemiology, monitoring, particle size, particulates, risk assessment, sensitive populations, Minnesota, chemical exposure, air pollutants, cardiopulmonary responses, health risks, human health effects, indoor exposure, lung, PM 2.5, stratospheric ozone, ambient air monitoring, exposure and effects, ambient air, ambient measurement methods, exposure, pulmonary disease, Utah (UT), developmental effects, epidemelogy, biological response, respiratory disease, air pollution, ambient monitoring, children, Human Health Risk Assessment, Massachusetts (MA), Washington (WA), particle exposure, lung cancer, biological mechanism , cardiopulmonary response, chronic effects, human exposure, inhalation, pulmonary, susceptibility, Illinois (IL), particulate exposure, assessment of exposure, ambient particle health effects, elderly, indoor air, inhaled, Connecticut (CT), epidemeology, human susceptibility, environmental health hazard, inhalation toxicology, gaseous co-polutants, cardiopulmonary, indoor air quality, inhaled particles, human health, cardiac ischemia, air quality, cardiovascular disease, dosimetry, human health risk, respiratory, genetic susceptibility, toxics, particle chemical composition

    Relevant Websites:

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    Progress and Final Reports:

    Original Abstract
  • 1999 Progress Report
  • 2000 Progress Report
  • 2001 Progress Report
  • 2003 Progress Report
  • 2004 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R827353    EPA Harvard Center for Ambient Particle Health Effects

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R827353C001 Assessing Human Exposures to Particulate and Gaseous Air Pollutants
    R827353C002 Quantifying Exposure Error and its Effect on Epidemiological Studies
    R827353C003 St. Louis Bus, Steubenville and Atlanta Studies
    R827353C004 Examining Conditions That Predispose Towards Acute Adverse Effects of Particulate Exposures
    R827353C005 Assessing Life-Shortening Associated with Exposure to Particulate Matter
    R827353C006 Investigating Chronic Effects of Exposure to Particulate Matter
    R827353C007 Determining the Effects of Particle Characteristics on Respiratory Health of Children
    R827353C008 Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac Ischemia
    R827353C009 Assessing Deposition of Ambient Particles in the Lung
    R827353C010 Relating Changes in Blood Viscosity, Other Clotting Parameters, Heart Rate, and Heart Rate Variability to Particulate and Criteria Gas Exposures
    R827353C011 Studies of Oxidant Mechanisms
    R827353C012 Modeling Relationships Between Mobile Source Particle Emissions and Population Exposures
    R827353C013 Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) Study
    R827353C014 Identifying the Physical and Chemical Properties of Particulate Matter Responsible for the Observed Adverse Health Effects
    R827353C015 Research Coordination Core
    R827353C016 Analytical and Facilities Core
    R827353C017 Technology Development and Transfer Core